Viral infections remain a major medical problem worldwide because of a lack of therapy, prevention or vaccination strategy and because of the rapid development of resistance. Viruses can be divided into two big groups, RNA-viruses and DNA-viruses, according to their genetic composition, which can then further be subdivided. Human pathogens include Adenovirus, Cytomegalovirus, Dengue virus, Ebola virus, Enterovirus, Epstein Barr Virus, Hantavirus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Herpes Simplex virus, Human Herpes Virus 6, 7 and 8, Human Immunodeficiency Virus, Human Metapneumovirus, Human Papilloma Virus, Influenza virus, Marburg virus, Nipah virus, Parvovirus B19, Polyoma BK virus, Polyoma JC virus, Respiratory Syncytial Virus, Varicella-Zoster virus, Variola, Coxsackie virus and others.
Human Papilloma Virus and other viruses are known to induce, or increase the predisposition to, cell proliferation disorders such as e.g. cancer tumours in human beings.
HIV-I (human immunodeficiency virus-1) is one of the problematic viral infections with an estimated 40 million people infected worldwide. However, many other viruses and virus families causing problematic disorders can be identified.
As an example, the family of the Herpesviridae includes important human pathogens like Herpes simplex virus (HSV) type 1 and 2, Varicella-Zoster virus (VZV), Cytomegalovirus (CMV), Epstein Barr virus (EBV) and human Herpes virus type 6, 7 and 8 (i.e. HHV-6, -7 and -8). These viruses cause disorders like Herpes Labialis, Herpes Genitalis, Herpes Encephalitis, Kaposi's sarcoma, Varicella, Zona, lymfomas and others. Current treatments consist of Acyclovir, Ganciclovir, Brivudin, Cidofovir and some other products.
Acyclic nucleoside phosphonates (ANPs), such as cidofovir (HPMPC) and adefovir (PMEA), were shown to inhibit the replication of HSV. Cidofovir (Vistide—Gilead Sciences) is used for the treatment of Cytomegalovirus (CMV) retinitis infection, which can cause blindness. However, it has been established that Cidofovir can be harmful to the kidneys. If someone is taking cidofovir, doctors need to watch for early signs of kidney problems using blood and urine tests. Decreased urination, increased thirst, or light-headedness after standing up can also be early warning signs of kidney problems. If a person already has kidney problems, cidofovir may not be an appropriate treatment for them. Furthermore, Cidofovir is given by intravenous infusion, directly into a vein in the arm. The infusion is given once a week for the first two weeks—this is called the induction treatment. The infusion is then given once every other week to keep the CMV infection under control. Long-term maintenance therapy is necessary. To try and prevent kidney damage, cidofovir is given with fluids. Probenecid, a drug that helps protect the kidneys, must also be given with cidofovir. Unfortunately, probenecid contains a sulfonyl group and can cause allergic reactions. Side effects caused by reactions to sulfonyl group-containing drugs can include rash and fever.
Also the Poxviruses comprise human and animal pathogens. The most important human pathogen in this family, the Variola virus (smallpox) has been the first human virus to be definitely eradicated, after mass vaccination under the control of the WHO. The last (natural) case of variola was described in October 1977 and the vaccination was definitely ceased in 1978. Meanwhile several strains of both variola major and variola minor were kept in reference centers in United States and Russia (formerly USSR), where they had to be destroyed after a decision of the World Health Assembly (WHO). However, in the last years, researchers were stimulated to develop new therapies as well as novel approaches for the prophylaxis or treatment of poxvirus infections due to the increased concern on the possible release of such viruses as mass destruction weapons by bioterrorists. Based on the possible release of infectious agents from repositories, variola among many other viruses and bacteria, is considered as one of the possible threats in a world population with a majority of people non immunized and lack of immunity that had not been boosted for several decades. Therefore, it was decided to intensify the development of better diagnostic tools, to generate new classes of vaccines responding to the actual rules of safety, and finally, to search for new and potent antiviral drugs. In order to reach these objectives, the destruction of variola stocks was postponed to allow the characterization of the different strains and to establish and validate different surrogate models using other (ortho)poxviruses for diagnostics, vaccines and antiviral drugs. In the mean time, other poxviruses for which no particular treatment is currently available have been recognized as of importance for human health, such as Monkeypox or Orf. Similarly, some poxviruses specific for animals, such as Camelpox, Cowpox or Orf could be of economical importance for some regions of the world.
As a conclusion, for many pathogenic viral infections, no efficient treatment is currently available and, moreover, the available anti-viral therapies or preventive measures are not sufficient in order to be able to cure, prevent or ameliorate the respective viral infections due to many reasons, like the occurrence of resistance and unfavorable pharmacokinetics or safety profiles.
Therefore, there is a clear need to enlarge the arsenal of antiviral molecules, especially against herpes viruses and poxviruses, and more especially against human herpesvirus 6, by developing new classes of compounds with better activity, a better resistance profile, a different and original mechanism of action, or improved pharmacokinetics or safety profiles to allow an optimal prevention or therapy of virus infections, as an example, in case of an extended spread of one or another poxvirus.
The present invention provides novel compounds that satisfy this need. More specifically, the current invention provides novel compounds which inhibit viral replication and which possess a higher activity, more specifically also against resistant viruses as compared to the compound HPMPC (Cidofovir) or which are less toxic such as for the kidney.